Diphenylalkanoether derivatives

ABSTRACT

Diphenylalkanoether and diphenylalkanone oximeether derivatives of the formula: ##STR1## wherein R 1  and R 2  are each independently an aryl group optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1  -C 4  alkyl, C 1  -C 4  alkoxy, nitro, cyano, di(C 1  -C 4 )alkylamino, amino, benzyloxy, hydroxyl, C 1  -C 4  alkylthio, C 1  -C 4  alkylsulfinyl, C 1  -C 4  alkysulfonyl, C 1  -C 4  alkanoylamino, C 1  -C 4  alkylmino and N-(C 1  -C 4 )alkyl-N-(C 1  -C 4 )alkanoylamino, Z 1  is a group of the formula: ##STR2## (wherein R 3  and R 4  are each independently a hydrogen atom, a C 1  -C 4  alkyl group or an ar(C 1  -C 4 )alkyl group or, when taken together with the adjacent nitrogen atom to which they are attached, represent a nitrogen-containing 5 to 7-membered saturated heterocyclic group optionally having an oxygen atom or an additional nitrogen atom as the hetero atom in additon to the said nitrogen atom and, in case of having the additional nitrogen atom, bearing a hydrogen atom, a C 1  -C 4   alkyl group, an ar(C 1  -C 4 )alkyl group or a phenyl group thereon), ##STR3## is a group of the formula: ##STR4## or the formula: ##STR5## A 1  is a C 2  -C 6  alkylene group and A 2  is a C 2  -C 4  alkylene group, and non-toxic, pharmaceutically acceptable acid addition salts thereof, which have cerebral vasodilating activity and antihypoxic activity.

This is a continuation-in-part application of our copending applicationSer. No. 136,565 filed on April 2, 1980, now U.S. Pat. No. 4,388,469,issued June 14, 1983.

This invention relates to diphenylalkanoether and diphenylalkanoneoximeether derivatives having cerebral vasodilating activity,antihypoxic activity and the like, and to preparation and use thereof.

The said diphenylalkanoether and diphenylalkanone oximeether derivativesare represented by the formula: ##STR6## wherein R¹ and R² are eachindependently an aryl group optionally substituted with 1 to 3substituents selected from the group consisting of halogen, C₁ -C₄alkyl, C₁ -C₄ alkoxy, nitro, cyano, di(C₁ -C₄) alkylamino, amino,benzyloxy, hydroxyl, C₁ -C₄ alkylthio, C₁ -C₄ alkylsulfinyl, C₁ -C₄alkylsulfonyl, C₁ -C₄ alkanoylamino, C₁ -C₄ alkylamino and N -(C₁-C₄)alkyl-N-(C₁ -C₄)alkanoylamino, Z¹ is a group of the formula:##STR7## (wherein R³ and R⁴ are each independently hydrogen atom, a C₁C₄ alkyl group or an ar(C₁ -C₄)alkyl group or, when taken together withthe adjacent nitrogen atom to which they are attached, represent anitrogen-containing 5 to 7-membered saturated heterocyclic groupoptionally having an oxygen atom or an additional nitrogen atom as thehetero atom in addition to the said nitrogen atom and, in case of havingthe additional nitrogen atom, bearing a hydrogen atom, a C₁ -C₄ alkylgroup, an ar(C₁ -C₄)alkyl group or a phenyl group thereon), ##STR8## isa group of the formula: ##STR9## or the formula: ##STR10## A¹ is a C₂-C₆ alkylene group and A² is a C₂ -C₄ alkylene group.

In the significances as defined above, the term "halogen" includesfluorine, chlorine, bromine and iodine; the term "ar(C₁ -C₄)alkyl"covers benzyl, phenylethyl, phenylisopropyl, etc.; and the term "aryl"means phenyl, pyridyl, thienyl, furyl, naphthyl or the like. The terms"C₁ C₄ alkyl" and "C₁ C₄ alkoxy" each signify straight or branched chainalkyl and alkoxy groups having from 1 to 4 carbon atoms (e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, etc.), and the terms "C₂ -C₆ alkylene" and "C₂ -C₄alkylene" mean straight or branched chain alkylene groups (e.g.ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,methylethylene, methylpropylene, etc.). The term "heterocyclic" includespyrrolidino, piperidino, homopiperidino, morpholino, piperazino, N-(C₁C₄)alkylpiperazino, N-ar(C₁ -C₄)alkylpiperazino, N-phenylpiperazino,etc.

In J. Pharmacol. Exptl. Therap., 112, 318-325 (1954), there aredisclosed diphenylalkanoether derivatives of the general formula:##STR11## wherein R is a hydrogen atom, a halogen atom, an alkyl groupor the like, which have antihistamine activity.

It has now unexpectedly been found that the diphenylalkanoether anddiphenylalkanone oximeether derivatives (I) have various excellentpharmacological activities other than antihistamine activity.Particularly, these ethers (I) show cerebral and coronary vasodilatingactivity, antihypoxic activity, antispasmodic activity, inhibitoryaction of aggregation of blood platelets, etc. Moreover, thepharmacological actions of the ethers (I) are very strong; for instance,the cerebral vasodilating actiyity in rats is extremely greater thanthat of the compound (A). Therefore, the ethers (I) are therapeuticallyuseful to treat cerebral or coronary arteriosclerosis, senile mentalindolence and the results of cerebral insufficiency. From this point ofview, preferred are those of the formula (I) wherein R¹ is phenyl orsubstituted phenyl, R² is phenyl and A¹ is trimethylene ortetramethylene. Particularly preferred are those of the formula (I) inwhich R¹ is phenyl or halophenyl, R² is phenyl, A¹ is trimethylene ortetramethylene and Z¹ is dimethylamino or piperidino.

Accordingly, a basic object of the present invention is to provide noveldiphenylalkanoether and diphenylalkanone oximeether derivatives (I)having cerebral basodilating activity, antihypoxic activity and thelike. Another object of the invention is to provide a process forproducting those ethers (I). These and other objects will be apparent tothose skilled in the art to which the present invention pertains fromthe foregoing and subsequent descriptions.

According to the present invention, the ethers (I) can be prepared (a)by reacting a compound of the formula: ##STR12## wherein R⁶ and R⁷ areeach independently an aryl group optionally substituted with 1 to 3substituents selected from the group consisting of halogen, C₁ -C₄alkyl, C₁ -C₄ alkoxy, nitro, cyano, di(C₁ C₄)alkylamino, benzyloxy, C₁-C₄ alkylthio and N-(C₁ -C₄)alkyl-N-(C₁ -C₄)alkanoylamino, ##STR13## isthe formula: ##STR14## or the formula: ##STR15## and A¹ is as definedabove with a halogen derivative of the formula:

    D.sup.1 --A.sup.2 --Z.sup.2                                (III)

wherein D¹ is a halogen atom, Z² is the same as defined with respect tothe symbol Z¹ but excluding the cases where at least one of R³ and R⁴ isa hydrogen atom and where Z² is an unsubstituted piperazino group and A²is as defined above and optionally subjecting the resulting product toreduction of the nitro group, debenzylation of the benzyloxy orbenzylamino group, acylation or alkylation of the amino group, oxidationof the C₁ -C₄ alkylthio group and/or demethylation of the N-(C₁-C₄)alkyl-N-methylamino group, or (b) by reacting a compound of theformula: ##STR16## wherein D² is a halogen atom, and R⁶, R⁷, A¹, A² and##STR17## are each as defined as defined above with an amine of theformula:

    H--Z.sup.1                                                 (V)

wherein Z¹ is as defined above and optionally subjecting the resultingproduct to reduction of the nitro group, debenzylation of the benzyloxyor benzylamino group, acylation or alkylation of the amino group,oxidation of the C₁ -C₄ alkylthio group and/or demethylation of theN-(C₁ -C₄)alkyl-N-methylamino group.

The diphenylalkanone oximeether derivatives of the formula: ##STR18##wherein R¹, R², A¹, A² and Z¹ are each as defined above can be alsoprepared by reacting a ketone derivative of the formula: ##STR19##wherein R¹, R² and A¹ are each as defined above with a hydroxylaminederivative of the formula:

    H.sub.2 N--O--A.sup.2 --Z.sup.1                            (VIII)

wherein A² and Z¹ are each as defined above and optionally subjectingthe resultant product to reduction of the nitro group, debenzylation ofthe benzyloxy or benzylamino group, acylation or alkylation of the aminogroup, oxidation of the C₁ -C₄ alkylthio group and/or demethylation ofthe N-(C₁ -C₄)alkyl-N-methylamino group.

The preparation process as above stated will be illustrated below indetail.

1. Production of the compound (I) from the compounds (II) and (III):

The compound (II) is reacted with the compound (III), usually in thepresence of an alkali (e.g. alkali metal hydride, alkali metal alkoxide,alkali metal amide, alkali metal) in an inert solvent (e.g. benzene,toluene, xylene, dimethylformamide, dimethylsulfoxide) at a temperatureranging from 30° C. to the refluxing temperature of the reaction system(preferably from 50° to 150° C.) to give the compound (I).

2. Production of the compound (I) from the compounds (IV) and (V):

The compound (IV) is reacted with the compound (V), usually in an inertsolvent at a temperature ranging from 0° C. to the refluxing temperatureto give the compound (I). Examples of the inert solvent include alcohols(e.g. methanol, ethanol), ethers (e.g. tetrahydrofuran, dioxane), amides(e.g. dimethylformamide, dimethylacetamide), aromatic hydrocarbons (e.g.benzene, toluene, xylene), ketones (e.g. methylethylketone,methylisobutylketone) and dimethylsulfoxide. The reaction is preferablyconducted in the presence of an alkali (e.g. alkali hydroxide, alkalicarbonate, alkali hydrogen carbonate, triethylamine, pyridine).

3. Production of the compound (VI) from the compounds (VII) and (VIII):

The compound (VII) is reacted with the compound (VIII), usually in aninert solvent in the presence of an alkali (e.g. alkali hydroxide,alkali carbonate, alkali hydrogen carbonate, triethylamine, pyridine) ata temperature ranging from 20° C. to the refluxing temperature of thereaction system to give the compound (VI). Examples of the inert solventare alkanols (e.g. methanol, ethanol, isopropanol), aqueous alkanols,dimethyl formamide, dimethylsulfoxide, etc.

4. Reduction of the nitro group and debenzylation of the benzyloxy orbenzylamino group:

These reactions may be accomplished by a per se conventional reductionprocedure such as catalytic hydrogenation using palladium on charcoal asthe catalyst. Debenzylation of the benzyloxy group can be also conductedby treatment with an acid (e.g. acetic acid, hydrochloric acid, Lewisacid).

5. Demethylation of the N-(C₁ -C₄)alkyl-N-methylamino group:

This reaction may be accomplished by a per se conventional procedure,preferably by treatment with ethyl chloroformate, followed by hydrolysiswith an alkali.

6. Acylation of the amino group:

Acylation of the amino group may be accomplished by a per seconventional procedure, preferably by treatment with the correspondingacid halide (e.g. acetyl chloride, propionyl chloride, butyryl chloride)in the presence of an alkali at a temperature ranging from 0° to 30° C.

7. Alkylation of the amino group:

Alkylation of the amino group may be accomplished by a per seconventional procedure, for example, by treatment with the correspondingalkyl halide (e.g. methyl bromide, ethyl bromide) in the presence of analkali at a temperature ranging from 20° C. to the refluxing temperatureof the reaction system.

8. Oxidation of the C₁ - C₄ alkylthio group:

Oxidation of the C₁ -C₄ alkylthio group can be conducted by treatmentwith hydrogen peroxide or a peracid in an inert solvent at a temperatureranging from 20° to 50° C.

The starting materials (II) and (IV) of this invention may be preparedby the following procedures: ##STR20## wherein R⁶, R⁷, A¹, A² and D² areeach as defined above.

In the foregoing scheme, the conversion of the compound (IX) into thecompound (II') can be accomplished by reduction of the former with ametal hydride (e.g. sodium borohydride, calcium borohydride) or withhydrogen in the presence of palladium on charcoal, nickel or platinumoxide. The conversion of the compound (IX) into the compound (II") maybe carried out by reaction of the former with hydroxylaminehydrochloride in the presence of an alkali. The reaction of the compound(II') or (II") with a compound of the formula:

    D.sup.3 --A.sup.2 --D.sup.2                                (X)

wherein D³ is a halogen atom and A² and D² are each as defined aboveaffords the compound (IV') or (IV"). The reaction may be effected in aninert solvent (e.g. benzene, toluene, xylene, dimethylformamide,dimethylsulfoxide) in the presence of an alkali at a temperature rangingfrom 30° C. to the refluxing temperature of the reaction system(preferably from 50° to 150° C.). Examples of the alkali are alkalimetal, alkali metal alkoxide, alkali metal amide, alkali metal hydride,etc.

Specific examples of the diphenylalkanoether and diphenylalkanoneoximeether derivatives (I) are as follows:

O-[3-(N,N-Dimethylamino)propyl]-1,4-diphenyl-1 -butanone oxime;

O-[2-(N,N-Dimethylamino)ethyl]-1,4-diphenyl-1 -butanone oxime;

O-[3-(4-Phenylpiperazino)propyl]-1,4-diphenyl-1 -butanone oxime;

O-[3-(N,N-Dimethylamino)propyl]-1-(p-fluorophenyl)-4-phenyl-1-butanoneoxime;

O-[3-(N,N-Dimethylamino)propyl]-1,3-diphenyl-1 -propanone oxime;

O-[2-(N,N-Diethylamino)ethyl]-1,4-diphenyl-1 -butanone oxime;

O-(3-Hexamethyleneiminopropyl)-1,4-diphenyl-1-butanone oxime;

O-(3-Piperidinopropyl)-1,4-diphenyl-1-butanone oxime;

O-[3-(N,N-Dimethylamino)propyl]-1,4-bis(3,4 -dimethylphenyl)-1-butanoneoxime;

O-[3-(N,N-Dimethylamino)propyl]-1-(3,4-dichlorophenyl)-4-phenyl-1-butanoneoxime;

O-[4-(N,N-Dimethylamino)butyl]-1,4-bis(o-chlorophenyl)-1-butanone oxime;

O-[3-(N,N-Dimethylamino)propyl]-1-(p-methoxyphenyl)-5-phenyl-1-pentanoneoxime;

O-[3-(N,N-Dimethylamino)propyl]-1-(m-methylphenyl)-6-phenyl-1-hexanoneoxime;

O-[3-(N,N-Dimethylamino)propyl]-1-(2-pyridinyl)-4 -phenyl-1-butanoneoxime;

O-[3-(N,N-Dimethylamino)propyl]-1,4-bis-thienyl-1 -butanone oxime;

O-[3-(N,N-Dimethylamino)propyl]-1-(p-dimethylaminophenyl)-4-phenyl-1-butanoneoxime;

O-[3-(N,N-Dimethylamino)propyl]-1-(p-hydroxyphenyl)-4-phenyl-1-butanoneoxime;

1-[3-(N,N-Dimethylamino)propoxy]-1,4-diphenyl-butane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-hydroxyphenyl)-4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-benzyloxyphenyl)-4-phenylbutane;

1-(3-Piperidinopropoxy)-1,4-diphenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1,5-diphenylpentane;

1-(3-Piperidinopropoxy)-1,5-diphenylpentane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(o-chlorophenyl)-4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-methoxyphenyl)-4-phenylbutane;

1-[2-(N,N-Diethylamino)ethoxy]-1,5-diphenyl-pentane;

1-[2-(N,N-Diethylamino)ethoxy]-1,4-diphenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-dimethylaminophenyl)-4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-thienyl-4 -phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(2-pyridinyl)-4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-isopropylsulfinylphenyl)-4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(4-pyridinyl)--phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-methylphenyl)-4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(m,p-dimethoxyphenyl)-4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1,3-diphenylpropane;

1-[3-(N,N-Dimethylamino)propoxy]-1-furyl-4-phenylbutane;

1-(3-Morpholinopropoxy)-1,4-diphenylbutane;

1-[3-(4-Phenylpiperazino)propoxy]-1,4-diphenylbutane;

1-(3-Benzylaminopropoxy)-1,4-diphenylbutane;

1-[3-(4-Methylpiperazino)propoxy]-1,4-diphenylbuyane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-isopropylsulfonylphenyl)-4-phenylbutane;

1-[3-(4-Benzylpiperazino)propoxy]-1,4-diphenylbutane;

1-[2-(N,N-Dimethylamino)ethoxy]-1,3-diphenylpropane;

1-(3-Aminopropoxy)-1,4-diphenylbutane;

1-[3-(N-Methylamino)propoxy]-1,4-diphenylbutane;

1-[2-(N,N-Dimethylamino)ethoxy]-1,5-diphenylpentane;

1-[2-(N,N-Dimethylamino)ethoxy]-1,4-diphenylbutane;

1-[4-(N,N-Dimethylamino)butoxy]-1,4-diphenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1,6-diphenylhexane;

1-[3-(N,N-Dimethylamino)propoxy]-1,7-diphenylheptane;

1-[3-(N-Methylamino)propoxy]-1-(p-fluorophenyl) -4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-cyanophenyl) -4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-nitrophenyl) -4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-aminophenyl) -4-phenylbutane;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-isopropylthiophenyl)-4-phenylbutane;

O-[3-(N,N-Dimethylamino)propyl]-1-(p-isopropylthiophenyl)-4-phenyl-1-butanone oxime;

O-[3-(N,N-Dimethylamino)propyl]-1-(p-acetaminophenyl)-4-phenyl-1-butanone oxime;

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-methylaminophenyl)-4-phenylbutane;

1-(3-Piperidinopropoxy)-1-thienyl-4-phenylbutane;

1-(3-Morpholinopropoxy)-1-thienyl-4-phenylbutane;

1-(3-Pyrrolidinopropoxy)-1,5-diphenylpentane;

1-(3-Pyrrolidinopropoxy)-1,4-diphenylbutane;

1-{3-[4-(p-Fluorophenyl)piperazino]propoxy}-1,4-diphenylbutane;

1-{3-[4-(p-Chlorophenyl)piperazino]propoxy}-1,4-diphenylbutane;

1-{3-[4-(p-Methylphenyl)piperazino]propoxy}-1,4-diphenylbutane;

1-{3-[4-(p-Hydroxyphenyl)piperazino]propoxy}-1,4-diphenylbutane;

1-(3-Hexamethyleneiminopropoxy)-1,5-diphenylpentane;

1-(3-Hexamethyleneiminopropoxy)-1,4-diphenylbutane;

1-[3-(2-Ethylpiperidino)propoxy]-1,4-diphenylbutane;

1-[3-(2 -Methylpiperidino)propoxy]-1,4-diphenylbutane;

1-[3-(2-Ethylpiperidino)propoxy]-1,5-diphenylpentane;

1-[3-(2-Methylpiperidino)propoxy]-1,5 -diphenylpentane;

1-(3-Piperidinopropoxy)-1-(p-fluorophenyl)-4-phenylbutane;

1-(3-Piperidinopropoxy)-1-(p-chlorophenyl)-4-phenylbutane;

1-(3-Piperidinopropoxy)-1-(p-methylphenyl)-4-phenylbutane;

1-(3-Piperidinopropoxy)-1-(p-hydroxyphenyl)-4-phenylbutane;

1-(3-Piperidinopropoxy)-1-(p-fluorophenyl)-5-phenylpentane;

1-(3-Piperidinopropoxy)-1-(p-chlorophenyl)-5-phenylpentane;

1-(3-Piperidinopropoxy)-1-(p-methylphenyl)-5-phenylpentane;

1-(3-Piperidinopropoxy)-1-(p-hydroxyphenyl)-5-phenylpentane;

1-(3-Morpholinopropoxy)-1-(p-fluorophenyl)-4-phenylbutane;

1-(3-Morpholinopropoxy)-1-(p-chlorophenyl)-4-phenylbutane;

1-(3-Morpholinopropoxy)-1-(p-methylphenyl)-4-phenylbutane;

1-(3-Morpholinopropoxy)-1-(p-hydroxyphenyl)-4-phenylbutane;

1-(3-Morpholinopropoxy)-1-(p-fluorophenyl)-5-phenylpentane;

1-(3-Morpholinopropoxy)-1-(p-chlorophenyl)-5-phenylpentane;

1-(3-Morpholinopropoxy)-1-(p-methylphenyl)-5-phenylpentane;

1-(3-Morpholinopropoxy)-1-(p-hydroxyphenyl)-5-phenylpentane;

1-(3-Morpholinopropoxy)-1,5-diphenylpentane;

O-[3-(N,N-Dimethylaminopropyl]-1-thienyl-4-phenyl 1-butanone oxime;

O-[3-(N,N-Dimethylaminopropyl]-1-furyl-4-phenyl -1-butanone oxime;

O-[3-(N-methyl-N-ethylamino)propyl]-1,5-diphenyl -1-pentanone oxime;

O-[3-(N-Methyl-N-ethylamino)propyl]-1,4-diphenyl-1-butanone oxime;

O-[3-(N-Methylpiperazino)propyl]-1,4-diphenyl-1-butanone oxime;

O-[3-(N-Methylpiperazino)propyl]-1,5-diphenyl-1-pentanone oxime;

O-[3-(N-Phenylpiperazino)propyl]-1,5-diphenyl-1-pentanone oxime;

O-(3-Morpholinopropyl)-1,4-diphenyl-1-butanone oxime;

O-(3-Morpholinopropyl)-1-(p-fluorophenyl)-4-phenyl-1-butanone oxime;

O-(3-Morpholinopropyl)-1-(p-chlorophenyl)-4-phenyl-1-butanone oxime;

O-(3-Morpholinopropyl)-1-(p-methylphenyl)-4-phenyl-1-butanone oxime;

O-(3-Morpholinopropyl)-1-(p-hydroxyphenyl)-4-phenyl-1-butanone oxime;

O-(3-Morpholinopropyl)-1,5-diphenyl-1-pentanone oxime;

O-(3-Morpholinopropyl)-1-(p-fluorophenyl)-5-phenyl-1-pentanone oxime;

O-(3-Morpholinopropyl)-1-(p-chlorophenyl)-5-phenyl-1-pentanone oxime;

O-(3-Morpholinopropyl)-1-(p-methylphenyl)-5-phenyl-1-pentanone oxime;

O-(3-Morpholinopropyl)-1-(p-hydroxyphenyl)-5-phenyl-1-pentanone oxime;

O-(3-Pyrrolidinopropyl)-1,4-diphenyl-1-butanone oxime;

O-[3-(2-Ethylpiperidino)propyl]-1,4-diphenyl-1-butanone oxime;

O-[3-(2-Methylpiperidino)propyl]-1,4-diphenyl-1-butanone oxime;

O-(3-Pyrrolidinopropyl)-1,5-diphenyl-1-pentanone oxime;

O-[3-(2-Ethylpiperidino)propyl]-1,5-diphenyl-1 -pentanone oxime;

O-[3-(2-Methylpiperidino)propyl]-1,5-diphenyl-1-pentanone oxime;

O-(3-Hexamethyleneiminopropyl)-1,5-diphenyl-1-pentanone oxime;

O-[2-(N,N-Diethylamino)ethyl]-1-(p-fluorophenyl) -4-phenyl-1-butanoneoxime;

O-[2-(N,N-Diethylamino)ethyl]-1-(p-chlorophenyl) -4-phenyl-1-butanoneoxime;

O-[2-(N,N-Diethylamino)ethyl]-1-(p-methylphenyl) -4-phenyl-1-butanoneoxime;

O-[2-(N,N-Diethylamino)ethyl]-1-(p-hydroxyphenyl) -4-phenyl-1-butanoneoxime;

O-[2-(N,N-Diethylamino)ethyl]-1-(p-fluorophenyl) -5-phenyl-1-pentanoneoxime;

O-[2-(N,N-Diethylamino)ethyl]-1-(p-chlorophenyl) -5-phenyl-1-pentanoneoxime;

O-[2-(N,N-Diethylamino)ethyl]-1-(p-methylphenyl) -5-phenyl-1-pentanoneoxime;

O-[2-(N,N-Diethylamino)ethyl]-1-(p-hydroxyphenyl) -5-phenyl-1-pentanoneoxime;

O-[2-(N,N-Diethylamino)ethyl]-1,5-diphenyl-1-pentanone oxime;

O-(3-Piperidinopropyl)-1-(p-fluorophenyl)-4-phenyl-1-butanone oxime;

O-(3-Piperidinopropyl)-1-(p-chlorophenyl)-4-phenyl-1-butanone oxime;

O-(3-Piperidinopropyl)-1-(p-methylphenyl)-4 -phenyl-1-butanone oxime;

O-(3-Piperidinopropyl)-1-(p-hydroxyphenyl)-4-phenyl-1-butanone oxime;

O-(3-Piperidinopropyl)-1-(p-fluorophenyl)-5-phenyl-1-pentanone oxime;

O-(3-Piperidinopropyl)-1-(p-chlorophenyl)-5-phenyl-1-pentanone oxime;

O-(3-Piperidinopropyl)-1-(p-methylphenyl)-5-phenyl-1-pentanone oxime;

O-(3-Piperidinopropyl)-1-(p-hydroxyphenyl)-5-phenyl-1-pentanone oxime;

O-(3-Piperidinopropyl)-1,5-diphenyl-1-pentanone oxime;

O-[2-(N,N-Dimethylamino)ethyl]-1,5-diphenyl -pentanone oxime;

O-[3-(N,N-Dimethylamino)propyl]-1,5-diphenyl-1-pentanone oxime, etc.

The thus prepared diphenylalkanoether and diphenylalkanone oximeetherderivatives (I) can be readily converted into their inorganic or organicacid addition salts by the conventional procedure.

For preparation of the pharmaceutical compositions, the ethers (I) ortheir salts may be mixed with carriers, diluents, lubricants, fillersand/or binders such as lactose, sucrose, calcium phosphate, starch,talcum, casein, magnesium stearate, methyl cellulose, polyglycols andtragacanth, sometimes together with stabilizers and emulsifying agents.The resulting mixture may be processed in a usual manner to tablets,capsules, pills, ampoules and the like. The usual oral dosage of theactive ingredient is from about 10 to 200 mg daily.

Practical and presently preferred embodiments of the invention areillustratively shown in the following Examples without limiting thescope of the invention in any way.

EXAMPLE 1

A mixture of 3.0 g of 1,4-diphenyl-1-butanone oxime, 5.0 g ofγ-dimethylaminopropyl chloride, 1.5 g of sodium hydride (65%) and 30 mlof toluene was heated under refluxing for 30 minutes. After cooling, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate, concentrated under reduced pressure and chromatographed onsilica gel to giveO-[3-(N,N-Dimethylamino)propyl]-1,4-diphenyl-1-butanone oxime. M.P.,122°-124° C. (oxalate); 97°-98.5° C. (fumarate); 99°-100.5° C.(citrate).

EXAMPLE 2

In a similar manner to Example 1, the following compounds were prepared:

O-[2-(N,N-Dimethylamino)ethyl]-1,4-diphenyl-1-butanone oxime, M.P.,121.5°-123° C. (oxalate);

O-[3-(N,N-Dimethylamino)propyl]-1-(p-fluorophenyl)-4-phenyl-1-butanoneoxime, M.P., 110°-111.5 ° C. (oxalate);

O-[3-(N,N-Dimethylamino)propyl]-1,3-diphenyl-1-propanone oxime, M.P.,123.5°-124° C. (oxalate);

O-[2-(N,N-Diethylamino)ethyl]-1,4-diphenyl-1-butanone oxime, M.P.,107°-108° C. (oxalate);

O-[3-(N,N-Dimethylamino)propyl]-1,5-diphenyl-1-pentanone oxime, M.P.,106°-111° C. (oxalate);

O-(3-Piperidinopropyl)-1,4-diphenyl-1-butanone oxime, M.P., 124°-125° C.(oxalate);

O-[3-(N,N-Dimethylamino)propyl]-1,4-bis(3,4-dimethylphenyl)-1-butanoneoxime, M.P., 107°-108° C. (oxalate);

O-[3-(N,N-Dimethylamino)propyl]-1-(3,4-dichlorophenyl)-4-phenyl-1-butanoneoxime, M.P., 106°-111 ° C. (oxalate), etc.

EXAMPLE 3

A mixture of 3.0 g of O-(3-chloropropyl)-1,4-diphenyl-1-butanone oxime,10 ml of N-phenylpiperazine, 3 g of potassium carbonate and 30 ml ofdimethylformamide was heated at 100° C. for 1 hour. After cooling, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate, concentrated under reduced pressure and chromatographed onsilica gel to giveO-[3-(4-phenylpiperazino)propyl]-1,4-diphenyl-1-butanone oxime. M.P.,153°-155° C. (oxalate).

EXAMPLE 4

In a similar manner to Example 3, the following compounds were prepared:

O-(3-Hexamethyleneiminopropyl)-1,4-diphenyl-1-butanone oxime, M.P.,110°-111° C. (oxalate), etc.

EXAMPLE 5

A mixture of 5.0 g of 1-(p-fluorophenyl)-4-phenyl -1-butanol, 10 g ofγ-dimethylaminopropyl chloride, 2.0 g of sodium hydride (65%) and 100 mlof toluene was heated under refluxing for 30 minutes. After cooling, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate, concentrated under reduced pressure and chromatographed onsilica gel to give1-[3-(N,N-dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenyl -butane.M.P., 80°-83° C. (fumarate).

EXAMPLE 6

In a similar manner to Example 5, the following compounds were prepared:

1-[3-(N,N-Dimethylamino)propoxy]-1-thienyl-4-phenylbutane, M.P., 70°-75°C. (fumarate);

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-benzyloxyphenyl)-4-phenylbutane,reddish oil;

1-[3-(N,N-Dimethylamino)propoxy]-1,4-diphenylbutane, M.P., 105°-107° C.(oxalate), 89°-92° C. (citrate);

1-[3-(N,N-Dimethylamino)propoxy]-1,5-diphenylpentane, M.P., 81°-85° C.(oxalate);

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-methoxyphenyl) -4-phenylbutane,M.P., 70°-73° C. (fumarate);

1-[3-(N,N-Dimethylamino)propoxy]-1-(4-pyridinyl)-4-phenylbutane, M.P.,103°-106° C. (fumarate);

1-[3-(N,N-Dimethylamino)propoxy]-1-(2-pyridinyl)-4-phenylbutane, M.P.,92°-94° C. (oxalate);

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-dimethylaminophenyl)-4-phenylbutane,M.P., 77°-80° C. (fumarate);

1-[3-(N,N-Dimethylamino)propoxy]-1-(p-methylphenyl) -4-phenylbutane,M.P., 98°-102° C. (fumarate);

1-[3-(N,N-Dimethylamino)propoxy]-1-(m,p-dimethoxyphenyl)-4-phenylbutane, M.P., 79°-85° C. (oxalate);

1-[3-(N,N-Dimethylamino)propoxy]-1,3-diphenylpropane, M.P., 103°-105° C.(fumarate);

1-[3-(N,N-Dimethylamino)propoxy]-1-furyl-4-phenylbutane, M.P., 75°-85°C. (oxalate);

1-[3-(N,N-Dimethylamino)propoxy]-1-(o-chlorophenyl) -4-phenylbutane,M.P., 65°-70° C. (fumarate);

1-[3-(Piperidinopropoxy)-1,5-diphenylpentane, M.P., 112°-118° C.(oxalate);

1(3-Piperidinopropoxy)-1,4-diphenylbutane, M.P., 81°-84° C. (fumarate);

1-[2-(N,N-Diethylamino)ethoxy]-1,5-diphenylpentane, M.P., 109°-112° C.(oxalate);

1-[2-(N,N-Dimethylamino)ethoxy]-1,4-diphenylbutane, M.P., 80°-81.5° C.(oxalate);

1-[2-(N,N-Dimethylamino)ethoxy]-1,3-diphenylpropane, M.P., 125°-126° C.(oxalate);

1-[3-(N,N-Dimethylamino)propoxy]-1-[p-(isopropylthio)phenyl]-4-phenylbutane,M.P., 96°-97° C. (fumarate);

1-[4-(N,N-Dimethylamino)butoxy]-1,4-diphenylbutane, M.P., 98°-99° C.(oxalate), etc.

EXAMPLE 7

A mixture of 1.5 g of 1-[3-(N,N-dimethylamino)-propoxy]-1-(p-benzyloxyphenyl)-4-phenylbutane obtained in Example 6,0.5 g of 10% palladium on charcoal (50% wet reagent), 1 g of acetic acidand 50 ml of ethanol was vigorously stirred in hydrogen atmosphere atroom temperature until the theoretical amount of hydrogen was consumed.The reaction mixture was poured into water, made alkaline with aqueousammonium hydroxide and extracted. After the catalyst was filtered off,the organic layer was washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give1-[3-(N,N-dimethylamino)propoxy]-1-(p-hydroxyphenyl)-4-phenylbutane.M.P., 91.5°-94.5° C. (oxalate).

EXAMPLE 8

A mixture of 1.5 g of 1-(3-chloropropoxy)-1,4-diphenylbutane, 7 ml ofmorpholine, 1,5 g of potassium carbonate and 15 ml of dimethylformamidewas heated at 100° C. for 1 hour. After cooling, the reaction mixturewas poured into water and extracted with ethyl acetate. The organiclayer was washed with water, dried over anhydrous sodium sulfate,concentrated under reduced pressure and chromatographed on silica gel togive 1-(3-morpholinopropoxy)-1,4-diphenylbutane. M.P., 138°-139° C.(oxalate).

The starting 1-(3-chloropropoxy)-1,4-diphenylbutane was prepared asfollows:

A mixture of 30 g of 1,4-diphenyl-1-butanol, 42 g of1-bromo-3-chloropropane, 9.5 g of sodium hydride (65%) and 400 ml oftoluene was heated under refluxing for 2 hours. After cooling, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give1-(3-chloropropoxy)-1,4-diphenylbutane.

EXAMPLE 9

In a similar manner to Example 8, the following compounds were prepared:

1-[3-(4-Methylpiperazino)propoxy]-1,4-diphenylbutane, M.P., 219°-221° C.(oxalate);

1-[3-(4-Phenylpiperazino)propoxy]-1,4-diphenylbutane, reddish oil, NMR δ(CDCl₃) (ppm), 3.32 (t), 4.20 (t);

1-[3-(Benzylamino)propoxy]-1,4-diphenylbutane, M.P., 97°-98° C.(oxalate);

1-[3-(Methylamino)propoxy]-1,4-diphenylbutane, M.P., 138°-140° C.(oxalate);

1-[3-(Isopropylamino)propoxy]-1,4-diphenylbutane, M.P., 107°-108° C.(oxalate);

1-(3-Aminopropoxy)-1,4-diphenylbutane, M.P., 143°-147° C. (oxalate),etc.

EXAMPLE 10

(a) A mixture of 1.0 g of1-[3-(N,N-dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane, 2.75g of potassium carbonate, 11 ml of ethyl chloroformate and 20 ml oftoluene was heated under refluxing for 2 hours. After cooling, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give 1-[3-(N-methyl-N-ethoxycarbonylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane.

(b) A mixture of 0.9 g of 1-[3-(N-methyl-N-ethoxycarbonylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane obtainedabove, 0.9 g of sodium hydroxide and 10 ml of dimethylsulfoxide washeated at 110° C. for 1 hour. After cooling, the reaction mixture waspoured into water and extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give 1-[3-(N-methylamino)-propoxy]-1-(p-fluorophenyl)-4-phenylbutane, reddish oil, NMR δ (CDCl₃)(ppm), 2.43 (s), 3.30 (t), 4.01 (t).

What is claimed is:
 1. A compound of the formula: ##STR21## wherein R¹is an unsubstituted phenyl, thienyl or furyl group or a phenyl groupsubstituted with 1 to 3 substituents selected from the group consistingof halogen, C₁ -C₄ alkyl and hydroxyl, R² is a phenyl group, Z¹ is agroup of the formula: ##STR22## wherein R³ and R⁴ are taken togetherwith the adjacent nitrogen atom to which they are attached to form apyrrolidino, piperidino, homopiperidino, morpholino, piperazino, N-(C₁-C₄) alkylpiperazino, N-phenyl (C₁ 14 C₄) alkylpiperazino orN-phenylpiperazino group, ##STR23## is a group of the formula ##STR24##A¹ is a C₃ -C₄ alkylene group, and A² is a C₂ -C₄ alkylene group or anon-toxic pharmaceutically acceptable acid addition salt thereof.
 2. Thecompound according to claim 1, wherein R¹ is a phenyl group or ahalophenyl group.
 3. The compound according to claim 1, wherein R¹ is aphenyl group or a halophenyl group and --NR³ R⁴ is a piperidino group.4. 1-(3-Piperidinopropoxy)-1,5-diphenylpentane, or a non-toxic,pharmaceutically acceptable acid addition salt thereof. 5.1-(3-Piperidinopropoxy)-1-(p-fluorophenyl)-5-phenylpentane, or anon-toxic, pharmaceutically acceptable acid addition salt thereof. 6.1-(3-Piperidinopropoxy)-1,4-diphenylbutane, or a non-toxic,pharmaceutically acceptable acid addition salt thereof. 7.1-(3-Piperidinopropoxy)-1-(p-fluorophenyl)-4-phenylbutane, or anon-toxic, pharmaceutically acceptable acid addition salt thereof.